Under previous funding, we have designed and built four breast CT scanners. The latest scanner, dubbed Doheny, makes use of a new detector system which delivers high spatial resolution and low noise breast CT images. The objectives of this proposal include software optimization and clinical trial comparisons of breast CT for screening normal risk women as well as high risk women. Software optimization: The first 2 aims of this project involve (1) the development of software which both corrects for the cupping artifacts associated with x-ray scatter, and restores the quantitative integrity of the breast CT images such that they have excellent gray-scale accuracy. A hardware-based scatter measurement procedure (reverse beam stop) has been implemented on the Doheny system; this Specific Aim will focus on optimizing the software corrections based upon the information provided by the reverse beam stop data. (2) Due to newly available components, the Doheny scanner has 4 times the spatial resolution of our earlier systems. In this aim, we will optimize th reconstruction kernel and matrix dimensions to assure maximal performance with respect to microcalcification detection, which requires very high spatial resolution. Clinical evaluation: Fou hundred women who will be having breast biopsy as part of their standard care (BIRADS 4 and 5) will be recruited to undergo additional imaging prior to biopsy, including (research) pre-and post- contrast enhanced breast CT imaging of both breasts, as well as (standard, FDA approved) contrast enhanced breast MRI (Specific Aim 3). In Aim 4, the potential of non-contrast enhanced breast CT will be compared using receiver operating characteristic (ROC) methodology against mammography alone, as well as with mammography + tomosynthesis. In Specific Aim 5, the breast CT images (including both pre-and post-contrast images) will be compared using ROC methodology against standard-of-care contrast-enhanced MRI (which includes both non-contrast and contrast images). The results of the clinical trials proposed in this investigation should provide strong evidence in regards to the potential of breast CT for breast cancer screening in the normal risk and high risk populations.